A key step in the synthesis of the reverse transcriptase inhibitor, (-)-6-chloro-4-cyclopropylenthynyl-4-triflouromethyl-1,4-dihydro-2H-3,1-be nzoxazin-2-one, also known as DMP-266, is the chiral addition to the 2-flouromethylcarbonyl-4-choloroanaline using cyclopropyl acetylene as a nucleophile, a chiral additive, a non-chiral additive, and an organic.
The syntheses of DMP-266 and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Pat. No. 5,519,021, and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
Additionally, several applications have been filed which disclose various aspects of the synthesis of (-)-6-chloro-4-cyclopropylethynyl-4-triflouromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one, including: 1) a process for the preparation of cyclopropylacetylene by cyclizing 5-halo-1-pentyne published on Aug. 1, 1996 in PCT Publication No. WO 96/22955; 2) a process for making the chiral alcohol, U.S. Ser. No. 60/035,462, filed Jan. 14, 1997; 3) the chiral additive, U.S. Ser. No. 60/034,926, filed Jan. 10, 1997; 4) the cyclization reaction, U.S. Ser. No. 60/037,059, filed Feb. 12, 1997; 5) the anti-solvent crystallization procedure, Case No. 19905PV2 (U.S. Serial No. unknown), filed May 23, 1997.
Several methods have been described in published literature for preparation of cyclopropylacetylene. C. E. Hudson and N. L. Bauld, J.A.C.S. 94:4, p.1158 (1972); J. Salaun, J.O.C. 41:7 p.1237 (1976); and W. Schoberth and M. Hanack, Synthesis (1972). p.703 disclose methods for the preparation of cyclopropylacetylene by dehydrohalogenating 1-cyclopropyl-1,1-dichloroethane. Miltzer, H. C. et al., Synthesis, 998 (1993) disclose a method for preparation of cyclopropylalkenes by halogenating an enolether, reacting the alkyl 1,2-dihaloether with propargyl magnesium bromide, and cyclizing to give a 2-alkoxy -1-ethynylcyclopropane. F. A. Carey and A. S. Court, J. Org. Chem., Vol. 37, No.12, (1972) p. 1926 disclose the use of a modified Wittig-Horner olefin synthesis for organcic transformations; D. J. Peterson, J. Org. Chem., Vol. 20C, No. 33, (1968) p. 780 describes the application of olfenation to make vinyl sulfides and H. Takeshita and T. Hatsui, J. Org. Chem., Vol. 43, No. 15, (1978) p. 3083 disclose the use of potassium 3-aminopropylamide in base-catalyzed prototropic reactions.
As illustrated by the Scheme below, Schoberth, et al., describes a method which resulted in about a 42% yield of the cyclopropylacetylene. ##STR1##
The instant invention discloses a more efficient process for the synthesis of this important substrate.